Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre, open-label, randomised, controlled phase II trial

Abstract

Background Advanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF ( BRAF -wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF -wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF -wt melanoma in a phase II, randomised and open-label trial. Patients and methods Patients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR). Results Participants were randomised to paclitaxel alone ( n = 38), paclitaxel and trametinib ( n = 36), or paclitaxel and pazopanib ( n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08–2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS ( P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96–1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms. Conclusion In this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF -wt melanoma improved PFS and substantially increased ORR but did not impact OS. This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.

Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience

“…The addition of chemotherapy to Pazopanib treatment has been tested in malignant melanoma with manageable toxicity. The foremost grade 3 toxicity was increase in alanine aminotransferase [21]. The combination of radiation therapy with pazopanib had been tested in the adjuvant treatment of breast cancer patient who developed less dermatological toxicity than matched control groups treated with radiation therapy alone [22].…”

Focus on the dabrafenib, vemurafenib, and trametinib in clinical outcome of melanoma: a systematic review and meta-analysis

“…There was no significant difference in PFS between paclitaxel plus pazopanib and single paclitaxel therapy. 27 Our meta-analysis study found that patients with targeted therapy were predisposed to a better clinical outcome in a patient with the positive BRAF gene mutation. Moreover, combination therapy has a better prognosis than monotherapy, probably due to the resistance mechanism.…”

Prognostic genes of melanoma identified by weighted gene co‑expression network analysis and drug repositioning using a network‑based method

“…In a phase II study of sunitinib in patients with advanced melanoma, 4/31 (13%) patients exhibited a partial response and 8 (26%) had stable disease (52). Pazopanib, a VEGF and platelet-derived growth factor inhibitor, has been used in combination with paclitaxel in a phase II study of patients with metastatic melanoma; the 6-month progression-free survival rate was 68%, and the 1-year overall survival rate was 48% (53). The objective response rate was 37%, comprising one complete and 20 partial responses (54).…”